<p>Hydroxyurea (HU) is an effective therapy for sickle cell disease (SCD) but remains underused worldwide. This scoping review aimed to identify geographical and multilevel barriers and facilitators influencing hydroxyurea initiation, uptake, and sustained use, using the Socio-Ecological Model (SEM) as a framework to guide the analysis and interpretation of findings. This scoping review followed the PRISMA-ScR guidelines. The Socio-Ecological Model (SEM) was used as an analytical framework to categorise and synthesise barriers and facilitators identified in the literature. PubMed, Scopus, Web of Science, and Google Scholar were searched for peer-reviewed studies. Eligible studies included quantitative, qualitative, and mixed-methods designs reporting barriers and/or facilitators to hydroxyurea use among individuals with SCD. We identified 30 studies across Africa, Asia, Europe, North America, and South America. Barriers to hydroxyurea use were reported across individual, caregiver, provider, health-system, and policy levels. Common barriers included negative beliefs, fear of adverse effects, limited knowledge, financial constraints, and gaps in access and monitoring. Facilitators included education, shared decision-making, peer support, provider training, guideline availability, insurance coverage, and improved drug access. Across settings, structural and health-system barriers were more consistently reported than individual-level factors, suggesting that hydroxyurea underutilisation is driven largely by system-level constraints rather than patient behaviour alone. Underutilisation of hydroxyurea in SCD reflects interacting socio-ecological barriers rather than patient non-adherence alone. Addressing these challenges will require coordinated, multilevel strategies that prioritise health-system strengthening alongside patient support to ensure sustained and equitable access to hydroxyurea.</p>